Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula I:

Ivacaftor was approved by FDA and marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets.
U.S. Pat. No. 7,495,103 (“the '103 patent”) discloses modulators of ATP-binding cassette transporters such as ivacaftor. The '103 patent further discloses a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds; however, ivacaftor process was not specifically disclosed. The '103 patent process includes condensation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with aniline in presence of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro phosphate methanaminium (HATU) and then purifying the obtained compound by HPLC. The process disclosed in the '103 patent is schematically represented as follows:

The '103 patent also discloses a process for the preparation of intermediates of ivacaftor such as 4-oxo-1,4-dihydro-3-quinoline carboxylic acid and 5-amino-2,4-di-(tert-butyl) phenol.
The process to prepare 4-oxo-1,4-dihydro-3-quinoline carboxylic acid involves the reaction of aniline with diethylethoxymethylene malonate followed by cyclization with large excess of polyphosphoric acid and phoshoryl chloride and then hydrolysis, which is schematically represented as follows:

The process to prepare 5-amino-2,4-di-(tert-butyl)phenol involves hydroxyl protection followed by nitration, deprotection of the hydroxyl group and reduction of nitro group, which is schematically represented as follows:

The synthesis of ivacaftor and its intermediates as discussed in the '103 patent has certain drawbacks as it involves:
a) use of tedious high performance liquid chromatography (HPLC) techniques for isolation of intermediates as well as final ivacaftor, makes the process quite expensive and not viable for large scale operations, and
b) use of high temperature reactions and large excess of phosphoryl chloride and strong acids like poly phosphoric acid leads to load on environment, which makes the process more complex, costly and highly unattractive particularly on commercial scale operations.
U.S. Patent Publication No. 2011/230519 (“the '519 publication”) discloses a process for preparation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid by reaction of aniline with diethylethoxymethylene malonate at 100-110° C. followed by cyclization in presence of phenyl ether at temperature 228-232° C. and hydrolysis, which is schematically represented as follows:

Disadvantages associated with the '519 publication is, usage of high temperature reactions such as cyclization at 228-232° C., which is difficult to achieve on large scale operations and further leads to the formation of unwanted by products and low product yields.
U.S. Patent Publication No. 2010/0267768 (“the '768 publication”) discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T3P®) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. The process disclosed in the '768 publication is schematically represented as follows:

The '768 publication discloses the use of highly expensive coupling reagent, propyl phosphonic anhydride; which in turn result to an increase in the manufacturing cost.
U.S. Patent Publication No. 2011/064811 (“the '811 publication”) discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in the presence of HBTU followed by the formation of ethanol crystalate, which is then treated with diethyl ether to yield ivacaftor as a solid. The process disclosed in the '811 publication is schematically represented as follows:

CN 103044263 discloses a process for the preparation of ivacaftor and the disclosed process schematically represented as follows:

Ivacaftor can exist in different polymorphic forms, which differs from each other in terms of stability, physical properties, spectral data and methods of preparation.
The '811 publication discloses polymorphs of ivacaftor such as crystalline ethanol solvate, Form A, Form B and amorphous Form.
The '519 publication discloses crystalline polymorph of ivacaftor such as Form C and preparation thereof.
U.S. Pat. No. 8,163,772 (“the '772 patent”) discloses solid forms of ivacaftor such as 2-methyl butyric acid (Form I), propylene glycol (Form II), PEG400.KOAc (Form III), lactic acid (Form IV), isobutyric acid (Form V), propionic acid (Form VI), ethanol (Form VII), 2-propanol (Form VIII), water (Form IX), besylate Form A (Form X), besylate Form B (Form XI), besylate Form D (Form XII), besylate Form E (Form XIII), besylate Form F (Form XIV), besylate Form A (Form X), hemibesylate (Form XV), and besylate monohydrate (Form XVI).
US Patent Publication No. 2013/281487 discloses crystalline solvates of ivacaftor, which are designated as Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form W and hydrate B. The said publication also disclosed process for their preparation.
It would be desirable to provide a process for the preparation of ivacaftor and intermediates thereof, which is simple and cost effective; in a convenient, cost efficient manner and a commercial scale.
The present invention provides a process for the preparation of ivacaftor using novel protected quinoline carboxylic acid compounds as intermediates, that process away from the aforementioned difficulties such as high temperature reactions and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride are avoided. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.